The invention described herein was made with Government support under grant numbers RO1 AR43356 and P30 AR44535 from the National Institutes of Health. Accordingly, the United States Government has certain rights in this invention.
Throughout this application, various publications are referenced within parentheses. Disclosures of these publications in their entireties are hereby incorporated by reference into this application to more fully describe the state of the art to which this invention pertains. Full bibliographic citations for these references may be found immediately preceding the claims.
Mastocytosis is a neoplastic disease caused at least in part by somatic mutations of the c-KIT proto-oncogene resulting in constitutive activation of its protein product, KIT, the receptor tyrosine kinase for stem cell factor. KIT stimulates mast cell proliferation and prevents apoptosis of neoplastic mast cells. To develop potential therapies for mastocytosis we used indolinones, small molecules which inhibit tyrosine kinases. An indolinone derivative with structure VI (see below) or structure VII inhibited wild-type KIT, but variably inhibited constitutively activated KIT mutants. The compounds with structure VI or structure VII were effective against KIT with juxtamembrane activating mutations. Furthermore, the compounds with structure VI or structure VII killed neoplastic mast cells expressing a juxtamembrane-mutated KIT, whereas the compound with structure VII killed neoplastic mast cells expressing KIT bearing a kinase domain mutation. These data show a direct correlation between inhibition of constitutively activated KIT and the death of neoplastic mast cells, and point to specific tyrosine kinase inhibitors as a novel therapy aimed directly at a cause of mastocytosis.
This invention provides a method of preventing or treating in a subject mastocytosis which comprises administering to the subject a therapeutically effective amount of a compound having the structure: 
or a pharmaceutically acceptable salt thereof so as to thereby prevent or treat mastocytosis in the subject, wherein
R1 is H or alkyl; R2 is O or S; R3 is hydrogen;
R4, R5, R6, and R7 are each independently hydrogen, alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO2NRRxe2x80x2, SO3R, SR, NO2, NRRxe2x80x2, OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH2)nCO2R, or CONRRxe2x80x2;
R8, R9, and R10 are each independently hydrogen, alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO2NRRxe2x80x2, SO3R, SR, NO2, NRRxe2x80x2, OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH2)nCO2R, or CONRRxe2x80x2;
n is 0-3; x is Br, Cl, F or I; each of R and Rxe2x80x2 is independently H, alkyl or aryl.
This invention provides a method of preventing or treating in a subject mastocytosis which comprises administering to the subject a therapeutically effective amount of a compound having the structure: 
or a pharmaceutically acceptable salt thereof so as to thereby prevent or treat mastocytosis in the subject, wherein R1 is H or alkyl; R2 is O or S; R3 is hydrogen;
R4, R5, R6, and R7 are each independently hydrogen, alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO2NRRxe2x80x2, SO3R, SR, NO2, NRRxe2x80x2, OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH2)nCO2R, or CONRRxe2x80x2;
R8, R9, R10 and R11 are each independently hydrogen, alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO2NRRxe2x80x2, SO3R, SR, NO2, NRRxe2x80x2, OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH2)nCO2R, or CONRRxe2x80x2;
Ra and Rb are each independently hydrogen, alkyl and C(O)R, or NRaRb taken together may be a heterocyclic ring of 3 to 8 atoms optionally substituted at one or more positions with hydrogen, alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO2NRRxe2x80x2, SO3R, SR, NO2, NRRxe2x80x2, OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH2)nCO2R, or CONRRxe2x80x2;
n is 0-3; x is Br, Cl, F or I; and each of R and Rxe2x80x2 is independently H, alkyl or aryl.
This invention provides a method of preventing or treating in a subject mastocytosis which comprises administering to the subject a therapeutically effective amount of a compound having the structure: 
or a pharmaceutically acceptable salt thereof so as to thereby prevent or treat mastocytosis in the subject, wherein R1 is H or alkyl; R2 is O or S; R3 is hydrogen;
R4, R5, R6, and R7 are each independently hydrogen, alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO2NRRxe2x80x2, SO3R, SR, NO2, NRRxe2x80x2, OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH2)nCO2R, or CONRRxe2x80x2;
A is a five membered heteroaryl ring thiophene, pyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, oxazole, isoxazole, thiazole, isothiazole, 2-sulfonylfuran, 4-alkylfuran, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3,4-oxatriazole, 1,2,3,5-oxatriazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,2,3,4-thiatriazole, 1,2,3,5-thiatriazole, or tetrazole, optionally substituted at one or more positions with alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO2NRRxe2x80x2, SO3R, SR, NO2, NRRxe2x80x2, OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH2)nCO2R, or CONRRxe2x80x2;
n is 0-3; x is Br, Cl, F or I; and each of R and Rxe2x80x2 is independently H, alkyl or aryl.
This invention provides a method of preventing or treating in a subject mastocytosis which comprises administering to the subject a therapeutically effective amount of a compound having the structure: 
or a pharmaceutically acceptable salt thereof so as to thereby prevent or treat mastocytosis in the subject, wherein R1 is H or alkyl; R2 is O or S; R3 is hydrogen;
R4, R5, R6, and R7 are each independently hydrogen, alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO2NRRxe2x80x2, SO3R, SR, NO2, NRRxe2x80x2, OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH2)nCO2R, or CONRRxe2x80x2;
R8, R9 and R10 and R11 are each independently hydrogen, alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO2NRRxe2x80x2, SO3R, SR, NO2, NRRxe2x80x2, OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH2)nCO2R, or CONRRxe2x80x2;
n is 0-3; x is Br, Cl, F or I; each of R and Rxe2x80x2 is independetly H, alkyl or aryl.
This invention provides a method of preventing or treating in a subject mastocytosis which comprises administering to the subject a therapeutically effective amount of a compound having the structure: 
or a pharmaceutically acceptable salt thereof so as to thereby prevent or treat mastocytosis in the subject, wherein RI is HI or alkyl; R2 is O or S; R3 is hydrogen;
R4, R5, R6, and R7 are each independently hydrogen, alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO2NRRxe2x80x2, SO3R, SR, NO2, NRR xe2x80x2, OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH2)nCO2R, or CONRRxe2x80x2;
R8, R9, R10 and R11 are each independently hydrogen, alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO2NRRxe2x80x2, SO3R, SR, NO2, NRRxe2x80x2, OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH2)nCO2R, or CONRRxe2x80x2;
n is 0-3; Z is Br, Cl, F, I, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, or tert-butyl; and each of R and Rxe2x80x2 is independently H, alkyl or aryl.
This invention provides a method of preventing or treating in a subject mastocytosis which comprises administering to the subject a therapeutically effective amount of a compound having the structure: 
or a pharmaceutically acceptable salt thereof so as to thereby prevent or treat mastocytosis in the subject.
This invention provides a method of preventing or treating in a subject mastocytosis which comprises administering to the subject a therapeutically effective amount of a compound having the structure: 
or a pharmaceutically acceptable salt thereof so as to thereby prevent or treat mastocytosis in the subject.
This invention provides a method of preventing or treating in a subject mastocytosis which comprises administering to the subject a therapeutically effective amount of a compound having the structure: 
or a pharmaceutically acceptable salt thereof so as to thereby prevent or treat mastocytosis in the subject.